rs114759137

Positions:

chr1-43432732-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365999.1(SZT2):c.5535T>G(p.Ser1845Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,613,606 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 53 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 42 hom. )

Consequence

SZT2
NM_001365999.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.43

Variant links:

Genes affected

SZT2 (HGNC:29040): (SZT2 subunit of KICSTOR complex) The protein encoded by this gene is expressed in the brain, predominantly in the parietal and frontal cortex as well as in dorsal root ganglia. It is localized to the peroxisome, and is implicated in resistance to oxidative stress. It likely functions by increasing superoxide dismutase (SOD) activity, but itself has no direct SOD activity. Studies in mice show that this gene confers low seizure threshold, and may also enhance epileptogenesis. [provided by RefSeq, Jun 2011]

SZT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SZT2. . Gene score misZ 2.5968 (greater than the threshold 3.09). Trascript score misZ 4.0086 (greater than threshold 3.09). GenCC has associacion of gene with undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017289519).

BP6

Variant 1-43432732-T-G is Benign according to our data. Variant chr1-43432732-T-G is described in ClinVar as [Benign]. Clinvar id is 260618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-43432732-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2149/151894) while in subpopulation AFR AF= 0.0493 (2041/41370). AF 95% confidence interval is 0.0476. There are 53 homozygotes in gnomad4. There are 997 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SZT2	NM_001365999.1 linkuse as main transcript	c.5535T>G	p.Ser1845Arg	missense_variant	39/72	ENST00000634258.3	NP_001352928.1
SZT2	NM_015284.4 linkuse as main transcript	c.5364T>G	p.Ser1788Arg	missense_variant	38/71		NP_056099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SZT2	ENST00000634258.3 linkuse as main transcript	c.5535T>G	p.Ser1845Arg	missense_variant	39/72	5	NM_001365999.1	ENSP00000489255	P1	Q5T011-1

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2138

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00499

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000833

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00360

AC:

902

AN:

250470

Hom.:

AF XY:

0.00263

AC XY:

356

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.0498

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00142

AC:

2078

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

918

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.0499

Gnomad4 AMR exome

AF:

0.00277

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.00323

GnomAD4 genome

AF:

0.0141

AC:

2149

AN:

151894

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

997

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.0493

Gnomad4 AMR

AF:

0.00491

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000625

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00238

Hom.:

Bravo

AF:

0.0164

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0508

AC:

224

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00435

AC:

528

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Developmental and epileptic encephalopathy, 18

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.55

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.5

.;N

Sift

Uncertain

0.019

.;D

Sift4G

Uncertain

0.020

D;D

Polyphen

0.0010

.;B

Vest4

0.14

MutPred

0.15

.;Loss of phosphorylation at S1788 (P = 0.0151);

MVP

0.17

MPC

0.29

ClinPred

0.0023

GERP RS

-4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.063

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over